Drug abuse is a major detrimental influence on society today, and stress is among the most prominent predisposing risk factors in drug abuse. Stress is known to affect a number of systems; but one system that plays a prominent role in both drug abuse and stress is the dopamine (DA) system. However, how stress affects the DA system has been somewhat controversial, in that neurochemical studies typically show stress-induced increases in mesolimbic DA systems, whereas electrophysiological studies more commonly report stress-induced inhibition of DA neurons. We have found that different stressor types can have markedly different effects on DA neuron activity. Thus, although acute noxious stimuli will transiently suppress individual DA neurons, maintained strong stressors such as repeated footshock or restraint stress will increase the number of DA neurons firing (i.e., population activity), leading to a hyper-responsivity of the DA system to other stimuli. In contrast, chronic inescapable cold stress or testing 24 hours after a restraint stress leads to a potent decrease in DA neuron population activity and the behavioral response to amphetamine. Moreover, these changes occur differentially across the medial (i.e., reward-related) -lateral (i.e., salience-related) extent of the ventral tegmental area (VTA) and its associated accumbens projection sites, which likely will have important functional implications. Thus, restraint stress increases DA neuron population activity across the medial-lateral VTA axis, whereas repeated footshock increase, and chronic cold decreases, population activity exclusively in the medial VTA. Moreover, these stressors show potent interactions, with exposure to chronic cold stress protecting the lateral DA system from the effects of restraint. In this proposal, we will examine how a range of stressors known to activate or attenuate the DA system affect DA neuron population activity across the medial-lateral extent of the VTA. We will assess the circuits involved in this process, which our preliminary results suggest that the ventral subiculum of the hippocampus is involved in stress-induced increases and the basolateral amygdala in stress-induced decreases in DA neuron activity. These studies address our central hypothesis: The type of stressor determines its impact on the DA system and drug abuse liability, with activation and suppression of DA system responsivity regulated in a VTA regionally-specific manner by specific afferent pathways. This will be done along 4 aims: 1) Test how each stressor affects DA neuron activity and amphetamine-induced locomotion, 2) Test how the ventral subiculum and the basolateral amygdala impact the stress-induced changes in the DA system, 3) Test how prior exposure to DA-attenuating stressors impact the DAergic response to activating stressors, and 4) examine how DA activating versus attenuating stressors affect amphetamine self-administration. These studies should provide important insights into how different stressors affect the DA system, the mechanisms underlying this interaction and, in turn, how they would impact the propensity to abuse drugs and provide insight into novel therapeutic approaches.